Ataxia-telangiectasia (A-T) is a rare, autosomal recessive human disorder characterized by cerebellar ataxia, immunodeficiency, cancer predisposition, recurrent sinopulmonary infections and chronic interstitial lung disease. The prognosis for this childhood disease is poor, and most patients do not survive beyond their teens. The most debilitating feature of A-T is progressive neurodegeneration;however, in addition to cancer, one of the leading causes of morbidity and mortality is respiratory system disease, including interstitial lung disease (ILD). Despite the prevalence of ILD as a cause of death in A-T patients, the underlying mechanisms that lead to this phenotype are not well understood. The gene mutated in A-T, ataxia-telangiectasia mutated (ATM), has been identified and encodes a large serine-threonine protein kinase. ATM is considered a "master controller" of cellular responses to DNA double strand breaks, and it is required for activation of cell cycle checkpoints, direct DNA repair events and/or apoptosis. ATM also plays important roles in the control of oxidative stress, and ATM deficiency leads to increased levels of highly reactive oxygen species as well as defects in antioxidant systems. Thus, the pleiotropic phenotypes observed in A-T patients, including ILD, are hypothesized to result from defective responses to DNA damage and/or the consequences of accumulated oxidative damage in mutant cells. The overall goals of this proposal are to elucidate the cellular and molecular mechanisms underlying ILD in A-T patients and to identify potential therapeutics to prevent or effectively treat this potentially fatal disease phenotype. To achieve these goals, we propose the following aims: (1) Develop and characterize a mouse model of A-T ILD using well-established and characterized methods to induce pulmonary fibrosis in animals. We have generated a conditionally inactivatable allele of ATM that can be deleted in specific tissues. Using this unique model system, we can examine the involvement of particular tissues and cell types in the initiation and progression of A-T lung disease;(2) Elucidate the roles of ATM in DNA damage responses in the lung and primary lung cell lines;and (3) Examine the efficacy of possible therapeutics on pulmonary fibrosis in the mouse model of A-T ILD. Together these studies will provide important insights into the causes of lung disease in A-T individuals and establish the effectiveness of potential treatments. In addition, our studies will define the DNA damage responses in the lung, findings that not only have relevance to phenotypes of A-T patients, but also to understanding the molecular bases underlying the severe lung toxicity caused by some chemotherapeutics. PUBLIC HEALTH RELEVANCE: Ataxia-telangiectasia (A-T) is an inherited childhood disease characterized by severe neurodegeneration, cancer predisposition, immunodeficiency and chronic lung disease. One of the most common causes of mortality in these patients is respiratory disease;however, this feature of A-T is not well understood. Thus, the goals of this research proposal are to gain a better understanding of the causes of chronic lung disease in these patients and to identify effective therapeutic strategies to treat this fatal symptom.